Natural immunoglobulins have been used in assays, diagnosis and, to a more limited extent, therapy. However, such uses, especially in therapy, have been hindered by the polyclonal nature of natural immunoglobulins. The advent of monoclonal antibodies of defined specificity increased the opportunities for therapeutic use. However, most monoclonal antibodies are produced following immunization of a rodent host animal with the target protein, and subsequent fusion of a rodent spleen cell producing the antibody of interest with a rodent myeloma cell. They are, therefore, essentially rodent proteins and as such are naturally immunogenic in humans, frequently giving rise to an undesirable immune response termed the HAMA (Human Anti-Mouse Antibody) response.
Previous attempts to decrease the immunogenicity of therapeutic antibodies have traditionally used a human template that is selected by the degree of homology to the donor antibody (the human antibody most homologous to the non-human antibody in the variable region is used as the template for humanization). Although this approach has been shown to work, it limits the possibility of selecting the best human template supporting the donor CDRs. Moreover, a CDR grafted humanized antibody prepared in this way may demonstrate a significantly decreased binding affinity.